DESCRIPTION (provided by Principal Investigator): Impaired thermogenesis and exposure to the insecticide DDT and its metabolite DDE are emerging risk factors for Type 2 diabetes (T2D). The Principal Investigator has found that mice developmentally exposed to DDT at levels within the range of human exposures develop impaired thermogenesis prior to T2D onset. These findings are concerning because the lifetime risk of T2D is over 30% in the USA, and T2D is rising rapidly among middle-aged adults who were in womb during peak DDT use. Developmental DDT exposures are particularly worrisome because the programming of lifelong metabolic tone that takes place during development is exquisitely sensitive to environmental insults. Further, over half the world's population is at risk of malaria infection, and the diabete epidemic has grown at stunning rates in countries where DDT is still in use for malaria control. There is a critical need to establish the mechanism by which DDT contributes to T2D risk. The Principal Investigator's long-term goal is to determine how the risk of metabolic disease is modified by developmental susceptibility to environmental exposures at levels found in humans. The overall objective of this application, which is the logical next step toward the long-term goal is to identify the mechanism(s) by which developmental exposure to DDT at doses common to humans contributes to T2D risk through impaired regulation of thermogenesis. This application aims to evaluate whether developmental DDT exposure changes epigenetic and/or adrenergic programs to cause deficient thermogenesis. Our approach is to evaluate how potential mechanistic changes in DNA methylation and sympathetic- innervation and tone are associated with impaired thermogenesis due to perinatal DDT exposure in mice and to model this in brown adipocyte culture. The proposed aims will be achieved through collaboration between Dr. Lein, who has expertise in toxicological effects on the development of peripheral nervous system, and the Principal Investigator, who has expertise in metabolic physiology and genomics techniques, while providing the training of two predoctoral trainees. Consultations with the UCD- Genome Center, NIDDK Mouse Metabolic Phenotyping Center, and an expert advisory committee further ensure the successful implementation of this application. Training in developmental cell lineage and in cellular imaging will position the Principal Investigator to address the aims of this application while also positioning her to achieve her long-term goals. Because the Principal Investigator is currently examining the association between perinatal DDT and DDE exposures with clinically-defined T2D in middle aged women, the proposed research has strong potential to lead to translational grants aimed at evaluating biomarkers of metabolic toxicity associated with developmental DDT and DDE exposure in humans. Defining biomarkers of perinatal DDT exposure that predispose individuals to T2D may potentially shift strategies for diagnosis, treatment and prevention of T2D. This work aligns with NIEHS Strategic Goal 2 to understand susceptibility to environmental disease across the lifespan, and with NIEHS Strategic Goal 1 to understand mechanisms in order to enable the development of prevention and intervention strategies.